NPM1 mutation reprograms leukemic transcription network via reshaping TAD topology

Area of Science:

• Molecular Biology
• Cancer Genetics
• Hematopoiesis

Background:

• C-terminal mutations of Nucleophosmin 1 (NPM1^C+) are implicated in acute myeloid leukemia (AML) pathogenesis.
• The precise molecular mechanisms of NPM1^C+-driven leukemogenesis are not fully understood.

Purpose of the Study:

• To elucidate the molecular mechanisms by which NPM1^C+ drives leukemogenesis.
• To investigate the role of CTCF-defined topologically associated domains (TADs) in NPM1^C+-mediated gene reprogramming.

Main Methods:

• Hematopoietic-specific NPM1^C+ knock-in mouse models.
• Analysis of topologically associated domain (TAD) topology.
• Chromatin accessibility assays.
• Gene expression profiling (HOX genes, cell cycle regulators).

Main Results:

• NPM1^C+ alters TAD topology, leading to aberrant HOX gene activation and cell cycle dysregulation.
• Disrupted chromatin accessibility and homeotic gene expression cause a myeloid differentiation block.
• Restoration of wild-type NPM1 reorganizes TADs, re-establishes differentiation, and prevents leukemogenesis.

Conclusions:

• NPM1^C+ reshapes CTCF-defined TAD topology to reprogram transcription programs essential for leukemic transformation.
• Altered TADs disrupt cell cycle regulation and myeloid differentiation, contributing to AML development.
• Targeting TAD reorganization offers a potential therapeutic strategy for NPM1^C+-driven AML.